Abstract
<jats:p>Predicting the most stable crystal structure of a given molecule remains a longstanding challenge. Crystal structure prediction (CSP) is the computational area of research seeking to identify all stable and metastable structures of a given compound using solely the two dimensional molecular connectivity diagram as input. The reliable stability ranking of hypothetical crystal structures at finite temperature requires the evaluation of the Gibbs free energies of a myriad computer-generated crystal structures. Current CSP workflows mostly rely on static (0 K) lattice energy differences due to the difficulties and computational cost associated with calculating entropic and other temperature-dependent free energy contributions. In some cases, a small number of structures are assessed via vibrational free energy calculation methods that either employ computationally demanding atomistic electronic structure calculations or force field approaches under the rigid-body approximation. There is a need to develop methods that offer a better compromise between accuracy and computational cost. In this work, we derive, for the first time, lattice dynamics expressions that allow for a fully atomistic treatment of molecular flexibility with a commonly used force field in CSP, relying on distributed multipole moments for the description of electrostatic interactions. We implement these expressions in the CrystalDynamics algorithm to calculate dispersion curves, phonon density of states and vibrational free energies and we demonstrate its application to molecular crystals of three compounds of increasing size and molecular flexibility. The analytical derivations underlying our proposed methodology result in an efficient and robust evaluation of the free energy of molecular crystals. Our work facilitates the study of relative stability as a function of temperature, enabling the evaluation of enantiotropic transitions between crystal forms. Thanks to its low computational cost our suggested method can be integrated into CSP protocols to bridge the gap between static lattice energies computed at 0 K and temperature-dependent free energies.</jats:p>